Control of Penile Erection by the Melanocortinergic System: Experimental Evidences and Therapeutic Perspectives

Penile erection is the ultimate vasculo-tissular response to an integrated and complex series of physiological processes elicited by psychological, neural, and hemodynamic events (Giuliano and Rampin, 2000; Saenz de Tejada, 2002). Upon sexual stimulation, penile erection, occurring in response to the activation of proerectile autonomic pathways, is greatly dependent on adequate inflow of blood to the erectile tissue and requires coordinated arterial endothelium-dependent vasodilatation and sinusoidal endothelium-dependent corporal smooth muscle relaxation. Most of the research efforts toward the treatment of erectile dysfunction (ED) have targeted the peripheral mechanisms of penile erection. These efforts have led to the identification of several compounds that can induce smooth muscle relaxation and erection by acting on cellular receptors (eg, prostaglandin E1) (Hedlund and Andersson, 1985; Stackl et al, 1988) or the intracellular machinery involved in the transduction of the signal (eg, sildenafil and other phosphodiesterase 5 inhibitors) (Giuliano, 2002). The registration in several countries of apomorphine for the treatment of ED has demonstrated the possibility of enhancing penile erection by acting elsewhere than on corpus cavernosum smooth muscle cells (Giuliano and Allard, 2002). The central nervous system (CNS) and, more specifically, the structures and neurotransmitters involved in the control of penile erection, represent, at least theoretically, a valuable alternative target for overcoming ED. In the CNS, several effectors involved in the control of erectile function have been identified. These include primarily dopamine, serotonin, noradrenaline, excitatory amino acids, oxytocin, and nitric oxide, among others (Moreland et al, 2000; Andersson, 2001). The present review is focused on the role of the melanocortinergic system in the regulation of penile erection. Several lines of evidence suggest that the melanocortinergic system may represent a potential valid pharmacological target for the treatment of ED. Because the interaction between the melanocortinergic system and erection seems to be neurally mediated, the review first briefly summarizes the role of the CNS in the command of erection. Sacral parasympathetic outflow, emanating from the intermediolateral cell column of the S2 to S4 spinal segments, is the proerectile pathway (Giuliano et al, 1995) (Figure). Sympathetic innervation of the pelvis, issuing from spinal segments T11 to L2, is responsible for the basal antierectile tone present during the flaccid state (Giuliano et al, 1997). Thus, it may be assumed that inhibition of the sympathetic component occurs during penile erection. Additionally, contraction of the ischiocavernosus and bulbospongiosus striated muscles, located at the penile crus and innervated by the motor pudendal nerve with cell bodies of motoneurons located in the Onuf nucleus, has a definite, contributory role in penile erection (Schmidt and Schmidt, 1993). Accordingly, the spinal coordination of various autonomic and somatic nuclei is required for a rigid and sustained penile erection (Rampin et al, 1997). The penis is also considered to be a sensory organ that sends information to the CNS via afferents. Indeed, the spinal autonomic nuclei controlling penile erection receive afferent information conveyed by afferent sensory fibers that originate from the penis and perigenital area, which are conveyed mainly by the dorsal nerve of the penis. The CNS maintains primary control over sexual motivation and penile erection (Giuliano et al, 2000). The precise sequence of neurotransmitter release within the CNS leading to penile erection is unknown. In the limbic system and, notably, in the nucleus accumbens, dopamine plays a key role in the anticipatory phase of sexual behavior. Participation of the noradrenergic system is also likely in the motivational aspect of sexual behavior. The medial preoptic area in the hypothalamus is essential for the display of sexual behavior, likely by integrating and redistributing information to hypothalamic and brainstem structures, such as the paraventricular nucleus (PVN) of the hypothalamus and the nucleus paragigantocellularis (nPGi) in the pons. In penile erection, dopamine activates oxytocinergic neurons in the PVN. Serotonergic projections from the nPGi to the SPN likely exert a tonic inhibition on erectile response, which are likely abolished upon sexual arousal by projections from the PVN to the nPGi. Melanocortins are bioactive peptides that are widely expressed in the CNS and in various peripheral tissues. These peptides are involved in the regulation of important physiological functions including food intake, energy homeostasis, and immune function. The discovery of the contribution of melanocortin peptides in the regulation of sexual function aroused new interest in the complex function of these peptides (Wikberg et al, 2000). The melanocortins comprise a group of natural peptides, all of which are derived from the precursor molecule propiomelanocortin (POMC). POMC is a polyhormone that can give rise to at least 8 distinct peptides whose biologic roles are incompletely delineated (Hadley and Haskell-Luevano, 1999). Cleavage at tetrabasic sites is an important regulatory step in the processing of POMC in the pituitary, where tissue-specific cleavage at the LysLysArgArg site in POMC produces either adrenocorticotropin (ACTH) in the anterior pituitary, or alpha-melanocyte-stimulating hormone (α-MSH) in the intermediate pituitary. Historically, POMC was thought to be produced solely by pituitary cells, but it has become apparent that POMC messenger RNA (mRNA) or POMC-derived peptides are expressed in extrapituitary tissues, such as the arcuate nucleus of the hypothalamus, the commissural nucleus of the brain stem, and the skin (Stengaard-Pedersen and Larsson, 1981; Nagahama et al, 1998; Hadley and Haskell-Luevano, 1999). In the spinal cord, immunoreactivity for the POMC-derived peptides ACTH and α-MSH has been detected in the dorsal horn and lamina × (Tsou et al, 1986). Melanocortins exert their diverse biological effects by binding to a distinct family of receptors belonging to the G-protein coupled receptors, which display 7 transmembrane regions as a hallmark. Five melanocortin receptors have been identified (MC-1 to MC-5) corresponding to the products of 5 separate genes with a highly conserved amino acid identity (Hadley and Haskell-Luevano, 1999; Adan and Gispen, 2000; Wikberg et al, 2000). Their activation leads to elevation of intracellular cyclic adenosine monophosphate through the activation of adenylate cyclase. While ACTH activates all 5 melanocortin receptors, α-MSH activates all receptors except the MC-2 receptor (Abdel-Malek, 2001). A unique property of the melanocortin system is the existence of endogenous antagonists of the melanocortin receptors (Lu et al, 1994). Indeed, hypothalamic neurons produce potent and selective antagonists of MC-3 and MC-4 receptors. These molecules, known as agouti or agouti-related peptide (AgRP), are expressed only in the arcuate nucleus of the hypothalamus by the same neurons that express neuropeptide Y (Shutter et al, 1997). In order to study the specific role of each melanocortin receptor subtype in the regulation of various physiological functions (Table), several highly potent and selective agonist and antagonist analogues have been generated using substitution of residues in the endogenous ligands. Although several analogues have been reported in the literature, the description here will be limited to those that have been studied for their effects on sexual functions. Melanotan-II (MT-II), which emerged from early studies, has helped our understanding of the physiological role of MC-3 and MC-4 receptors in the control of penile erection. This compound is a cyclic peptide analogue of α-MSH that expresses agonistic activity at the MC-4 receptor, which is also an effective agonist on MC-1, MC-3, and MC-5 receptors (Wikberg et al, 2000). PT-141, which is the first metabolite of MT-II, is another synthetic peptide analogue with an agonist activity on melanocortin receptors, including the MC-3 and MC-4 receptors (Molinoff et al, 2003). Recently, a high-affinity tetrahydroisoquinoline (THIQ) agonist for the MC-4 receptor has been described (Sebhat et al, 2002). This ligand has a greater than 100-fold selectivity for the MC-4 receptor over the other melanocortin receptors. The group of synthetic melanocortin receptor antagonists is represented by SHU9119 and two HS compounds (Fan et al, 1997; Kask et al, 1998; Schioth et al, 1999; Wikberg et al, 2000). SHU9119 antagonizes the MC-4 receptor at least three-fold more potently than the MC-3 receptor. HS014 is a potent and selective antagonist of the MC-4 receptor. This ligand has approximately 20-fold higher affinity for the MC-4 receptor than the MC-3 receptor. Another antagonist selective for the MC-4 receptor is HS024, which is about 10-fold more potent for the MC-4 receptor compared to HS014. The MC-3 and MC-4 receptors are abundantly expressed in the CNS, where they play a pivotal role in the regulation of feeding behavior and energy homeostasis. As shown in the Figure, these receptors are located in several nuclei involved in the control of erectile function. Expression of the MC-3 receptor is found mainly in the hypothalamus, thalamus, brainstem, and cortex (Roselli-Rehfuss et al, 1993; Lindblom et al, 1998), whereas the MC-4 receptor has a wider distribution and is found essentially in all regions of the brain, including the cortex, thalamus, hypothalamus, and brainstem (Mountjoy et al, 1994; Kishi et al, 2003). In the spinal cord, the MC-4 receptor was the only melanocortin receptor subtype for which mRNA was detectable. Mountjoy and Wild (1998) found that the MC-4 receptor mRNA was expressed throughout the spinal cord of the rat. Strong expression was observed in the intermediate zone of the thoracic spinal cord, particularly its lateral part, and in the ventral horn. A strong and dense signal was also observed over the outer part of the dorsal horn, and diffuse labeling was observed in the dorsal root ganglia. Over several lower segments of the spinal cord, a strong, dense signal was distributed as a continuous column in the gray matter on either side of the midline. Van der Kraan et al (1999) analyzed the expression of the MC-4 receptor in rat lumbar spinal cord (L4—L6) and found that levels of expression were greatest in area × and substantia gelatinosa; intermediate in laminae III, IV (medial aspect), V-VI, VII, and VIII; and low in the region of the ventrolateral motor neurons (lamina IX). MC-4 receptor mRNA in situ signal was observed throughout the gray matter, but a dense signal was also observed in lamina I-II. Surprisingly, in male rats, the MC-4 receptor was also found in several peripheral tissues that have been implicated in the control of penile erection, including the penis itself, and the major pelvic ganglion (the equivalent in the rat of the pelvic plexus in humans, which is a major relay center for the autonomic pathways to the penis). More detailed mapping of the tissue distribution of MC-4 receptor using in situ hybridization was possible in human and rat penis, and MC-4 receptor mRNA was found at free nerve endings and mechanoreceptors in both the corpus cavernosum and glans of the penis (Van der Ploeg et al, 2002). This intriguing finding suggests that melanocortins may contribute to the control of erectile function and male sexual behavior through peripheral action. The presence of MC-5 receptors in rat reproductive exocrine glands also supports the idea of functional coherence between the peripheral and central effects of the melanocortin peptides in the regulation of sexual behavior (van der Kraan et al, 1998). The ability of ACTH and α-MSH to cause sexual excitation has been established in different species, including rats, rabbits, cats, dogs, and monkeys. In a number of reports, cerebroventricular injection of ACTH or α-MSH in a low range (1–10 μg) has been shown to induce penile erection, stretching, and yawning (Bertolini and Gessa, 1981; Serra et al, 1987; Argiolas et al, 2000) in conscious animals. In rabbits, the sexual response beginning 15 to 60 minutes after administration of ACTH or α-MSH is characterized by recurrent episodes of penile erection accompanied by copulatory movements, ending with ejaculation (Bertolini and Gessa, 1981). In sexually experienced male rats, ACTH decreases the ejaculation latency and the number of mounts and intromissions prior to ejaculation during mating experiments. The effects of melanocortins on erection appear to be androgen-dependent because the erectile effect of ACTH was abolished by castration and restored by testosterone replacement (Bertolini and Gessa, 1981; Bertolini et al, 2001). Erections induced by direct administration of ACTH and α-MSH in the lateral or third cerebral ventricles indicates the pivotal role of the brain in this response. Furthermore, intracerebral injection of very low doses of MT-II (Wessels et al, 2003), THIQ (Martin et al, 2002), and PT-141 (Molinoff et al, 2003) recapitulate the erectogenic effects of systemic administration of these agents. The role of the brain is also demonstrated by induced by both ACTH and α-MSH the hypothalamic region of the third including the paraventricular nucleus of the hypothalamus, the nucleus, the nucleus, and the anterior hypothalamic of the paraventricular nucleus in the proerectile effect of ACTH is because of this nucleus yawning and penile erection induced by apomorphine but by ACTH et al, In and penile erection in rats, but the of such et al, Recently, identification of MC-4 receptors in the spinal cord has led to the of the effects of administration of melanocortins on erection. In rats, in was found α-MSH μg) was et al, 2002). In with this and have reported that administration of MT-II in conscious induced a in the of penile Surprisingly, MT-II at the same doses was found to be more in than The for the between the two but it may to the presence of in the or to a in the site of The between the melanocortin analogues in each study may also for these Indeed, in to MT-II proerectile effects at very low doses have the proerectile effect of MT-II in As the presence of the melanocortin receptors in the free nerve endings and mechanoreceptors of erectile tissues is of an role of the melanocortin peptides in the control of penile erection via a peripheral action. found that administration of MT-II in in penile in In this MT-II also effect on the erectile elicited by an of the which led the to effect of this agonist of the MC-4 receptor on the mechanisms of erection. These are in with in in which MT-II to the relaxation of et al, 2001). the MC-4 receptor agonist THIQ it rat erectile tissue (Van der Ploeg et al, 2002). The of these that melanocortin receptors present in erectile tissue are involved in the erectogenic effect of the that MC-4 receptors appear to be expressed in the sensory it be that melanocortins may erection through an effect on the afferent nerve The to that melanocortins erection through a CNS action. Several of this interaction between the melanocortin system and erectile function the effect of melanocortins on penile erection in the presence or of sexual has been In this have observed that in rats, administration of MT-II is to erectile and the erectile elicited by nerve is these two effects and are to the activation of the same or they the of different the same melanocortin receptor subtype these effects also unknown. The expression of MC-3 and MC-4 receptors in regions of the brain involved in the control of sexual behavior was the first that these two receptor a functional Furthermore, the that inhibition of in by central administration of the antagonist SHU9119 evidence for the role of these two receptor in the erectogenic effects of melanocortins et al, 2003). a series of have been by several in order to the role of each receptor subtype in the control of erection. the selective MC-4 receptor antagonist it has been shown that stretching, and yawning induced by ACTH and α-MSH are by the MC-4 receptor, whereas penile erection was et al, 1998). on these it has been that the MC-3 receptor may the proerectile effects of the proerectile of a selective MC-3 receptor agonist or the effects of selective of MC-3 receptor on the erectile response to melanocortins are et al, 2003). In more to a role for the CNS MC-4 receptor in the erectogenic effects of Indeed, selective activation of the MC-4 receptor using the THIQ compound erection in an (Van der Ploeg et al, 2002). The ability of the MC-4 agonist THIQ to erectile was in MC-4 which indicates that the effect observed is MC-4 Furthermore, administration of THIQ the (Martin et al, 2002). the which a penile erection is in a conscious rat by of the penile THIQ compound was also found to the number of penile in a (Martin et al, 2002). cerebroventricular administration of an MC-4 antagonist the proerectile effects of The ability of SHU9119 to the proerectile effects of MT-II, by the same suggests that the spinal of MT-II is by the melanocortin receptors and by other proerectile receptors 2003). The MC-4 receptor is the likely because it is the only melanocortin receptor subtype that has been located in the spinal The of more selective or on this The copulatory behavior of MC-4 is an in of a role for the MC-4 receptor subtype in the control of male sexual function. Indeed, Van der Ploeg and have male MC-4 and with and found that MC-4 have an and latency compared with control of the MC-4 a in that of the MC-4 during a compared with 5 of that the MC-4 are it is to a the copulatory behavior described in these is to the of the MC-4 receptor or to the presence of which is known to sexual The mechanisms involved in the regulation of penile erection by melanocortins are have shown that melanocortins may a different from the by This is on the that cerebroventricular injection of an antagonist can the erectile activity induced by apomorphine or central oxytocin, but the erectile activity induced by ACTH et al, et al found that erectile were of oxytocinergic because an antagonist to the receptor effect on the erectile to In to these et al have shown that systemic administration of a selective receptor the proerectile effects of the MC-4 receptor agonist Furthermore, administration of the penile induced by These suggest that the oxytocinergic system may play a pivotal role in the control of erectile function by the MC-4 receptor. are required to the between the role of the oxytocinergic pathway in the erectile effects of THIQ ACTH and Several have shown the of various neurotransmitters and in the control of erectile function by Indeed, the penile induced by ACTH were by with the nitric et al, it has been that activation of nitric in the CNS may represent a pathway in the control of erection by oxytocin, and also to be involved in penile erection because administration of the the erectile effects of ACTH et al, of in the paraventricular nucleus of the hypothalamus to the erection induced by ACTH et al, is also evidence other mechanisms in the control of erection by melanocortins as by the that penile to ACTH are by et al, 1995) and receptor antagonists et al, melanocortins may several other distinct and mechanisms in the CNS that to the of a penile erection. has been interest of in the of selective melanocortin receptor in the treatment of ED. is research for new and selective analogues of the melanocortin receptors. melanocortin receptor MT-II and PT-141 (the metabolite of have early for this were first reported as an in a study to the effect of MT-II on skin in et al, As a the effects of MT-II on ED were by et al 2000). In a study of with ED et al, MT-II and were each by injection for a of sexual and MT-II were by at least the with ED MT-II at doses from to 8 rigid by The to of erection from 15 to and the an of This proerectile effect of MT-II appear to be limited to of ED. Indeed, it has been shown that a of MT-II is effective in ED et al, 2000). In this study of with an erection at least of two of MT-II sexual The of after MT-II administration from minutes to of erectile In this were to their of sexual during the The erectogenic effects of MT-II were with a in sexual after of compared to of these have demonstrated that MT-II a proerectile activity in with ED of various The sexual reported with MT-II stretching, and were reported more after of MT-II than and only experienced The of this agonist stretching, and Although of episodes of with The of MT-II about the and potential of this The effect of PT-141 on penile erection in has been reported by et al PT-141 was at doses from to to in a and the of the was by a This study was also sexual that of PT-141 in a a minutes after the administration with a of The particularly to of erectile activity to minutes after with the known of to PT-141 erectile Indeed, the of with greater than was approximately minutes in the with of PT-141 compared to minutes in the The effect of PT-141 has also been reported in a of with to ED (Molinoff et al, 2003). This study sexual A in erectile activity was observed in PT-141 as compared to The of erection and penile were also after PT-141 These in a of with ED for the potential of be that to side effects have been reported after PT-141 administration in either or in with ED. The important role of the melanocortinergic system in the regulation of erectile function is Melanocortins control penile erection through an in the CNS, but the precise role of the spinal and and pathways in this regulation are The presence of melanocortin receptors in the peripheral nerve of the penis suggest that they may also through the peripheral nervous are also and the melanocortin receptor involved in sexual function. suggest that the MC-3 receptor the proerectile effects of whereas other suggest the of the MC-4 receptor. A between the MC-3 and MC-4 receptors in the control of erectile function may also because of each subtype to produce greater than activation of erectile activity 2000). The mechanisms that the proerectile effects of the melanocortins are also of the of and the involved will be of for the discovery of new and more for the treatment of ED. the receptor subtype that the effects of the melanocortins on erection to a targeted to this receptor. a it is also important to the melanocortins or induce This potential for or is an important and unique pharmacological property that be either in or as an to phosphodiesterase 5 The effect of melanocortins on sexual is also and have demonstrated both and of MT-II and PT-141 in with ED. that PT-141 may be the of the two on highly selective melanocortin receptor agonist may be in of these in derived from important aspect of this research on the of the low of analogues after administration and the for for melanocortin receptors that be This of the first new and effective and acting for the treatment of ED. to for in the and to for